Cornelia de Lange Syndrome (CdLS) is a devastating genetic syndrome that occurs approximately once per 10,000 births and displays slow growth, physical deformities in limbs, heart and kidney, mental retardation, speech deficits and autism (Dorsett and Krantz (2009) Ann NY Acad. Sci. 1151:22-37). It is rarely inherited, and usually caused by sporadic dominant mutations. CdLS is associated with poor growth and diverse physical deformities and mental deficits. CdLS displays many features commonly seen in isolation in sporadic birth defects, and thus treatments developed for CdLS may also be beneficial for developmental disorders of unknown etiology. CdLS birth defects include clinically diagnostic facial features, upper limb deformities, and gut, heart, and kidney abnormalities. Other deficits include mental retardation (average IQ in the 50's), speech difficulties, and autism. CdLS has a significant lifestyle and financial impact on families, as CdLS individuals often require fulltime care for their entire life.
CdLS is caused by mutations in genes that encode proteins that mediate sister chromatid cohesion and control gene expression (Dorsett and Krantz 2009 Ann N Y Acad. Sci. 1151:22-37). Over half the cases are caused by dominant loss-of-function mutations in NIPBL, the human ortholog of the Nipped-B Drosophila gene. Some 5% are caused by dominant mild missense mutations in SMC1A. SMC1A is a subunit of the cohesin protein complex that holds sister chromatids together until a cell divides, and NIPBL loads cohesin onto chromosomes. Changes in gene expression are the likely source of the CdLS birth defects. In model organisms and CdLS cells, many genes important for growth and development are dysregulated. The Inventors reasoned that if CdLS can be diagnosed early, preferably upon birth, or prenatally, a drug therapy based on early intervention may ameliorate some postnatal growth and developmental deficits. The reduction in NIPBL expression in CdLS is 30% or less, and thus a modest increase in NIPBL function will likely be beneficial. Moreover, treating the source deficit would be more effective than trying to treat the many downstream consequences. Current evidence suggests that brain development is particularly plastic, and thus it may be possible to treat older individuals. Cognitive function is the most critical for self-care, and treatments than can improve these functions will reduce the impact on CdLS families.
There are currently no treatments for CdLS that address the root cause of the syndrome and improve physical growth and mental development. These are the critical phenotypes that greatly impact the ability of individuals with CdLS to function normally, and the abilities of their families to care for them over many years. Using yeast, Drosophila, and mouse cells, the Inventors have discovered a rapid, cost-effective method for screening potential therapeutic compounds for the treatment of CdLS, and have also identified specific compounds, useful for the treatment of CdLS.